The Precision Approach to healthCARE enrollment Site (PA CARES) will engage the 2.9 million patients from rural upper Appalachia to suburban and urban environments with diverse sociodemographic characteristics who receive care from the University of Pittsburgh Medical Center (UPMC). UPMC, the largest non-profit integrated health delivery system in the US, comprises 22 hospitals, >500 outpatient facilities, 17 senior communities, and a health insurance plan (2.8M members) in a 29-county region of Pennsylvania plus part of Ohio and West Virginia. We will leverage several large-scale participant recruitment and informatics initiatives at the University of Pittsburgh to enroll 175,000 participants in the Precision Medicine Initiative (PMI) Cohort Program. During Year 1, we will rapidly enroll 10,000 participants from our health system-wide Research Participant Registry that currently includes >101K individuals who have consented to be re-contacted about enrolling in research studies. Our ongoing strategic initiatives will support the engagement and enrollment of 165K participants in Years 2-5. Our work with Wondros, a design-thinking-based production company, on a storytelling and messaging program (Pitt+Me?) to engage Pennsylvanians in research will be customized to communicate the PA CARES message to UPMC patients. We will continue partnering with The Chartis Group (project management), TrialSpark (social media-based participant recruitment and eScheduling), and Flipside Media (online e-consent) to ensure the efficient engagement and enrollment of diverse participants at 11 geographically dispersed centers in a variety of UPMC (e.g., obstetrical delivery units, emergency departments, urgent care facilities, clinics, hospitals) and community (e.g., Giant Eagle community pharmacies, Urban League of Greater Pittsburgh, >150 organizations) settings. Our nationally recognized informatics expertise in collecting, harmonizing, merging, and curating data from the extensive UPMC electronic health record (EHR) and diverse research sources and our experience creating a common ontology and data model for linking EHR data in national NIH- and PCORI-funded data networks will enable us to curate and store enrollee EHR and other data and transmit them to the PMI Coordinating Center on schedule. Our informatics tools will also facilitate the collection, tracking, and shipment of biospecimens to the PMI Biobank. Our robust track record documents our ability to efficiently enroll 175K diverse individuals from a single healthcare system using streamlined processes and to contribute to the successful achievement of the broader goals of the PMI, including the advancement of precision medicine.